Process for preparing 3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines

ABSTRACT

The present invention relates to a novel process for preparing 3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines which are known as intermediates for preparing compounds having fungicidal properties (WO 95-04728). Furthermore, the invention relates to novel 3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines, to novel intermediates for their preparation and to a plurality of processes for preparing the novel intermediates.

This application is a division of U.S. Ser. No. 09/528,228, which wasfiled on Mar. 17, 2000, and is now U.S. Pat. No. 6,335,454, which is, inturn a division of U.S. Ser. No. 09/186,708, which was filed on Nov. 5,1998, and is now U.S. Pat. No. 6,093,837, which is, in turn, a divisionof U.S. Ser. No. 08/982,531, which was filed on Dec. 2, 1997, and is nowU.S. Pat. No. 6,005,104.

The present invention relates to a novel process for preparing3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines which are known asintermediates for preparing compounds having fungicidal properties (WO95-04728). Furthermore, the invention relates to novel3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines, to novel intermediatesfor their preparation and to a plurality of processes for preparing thenovel intermediates.

It has already been disclosed that certain3-(1-hydroxyphenyl-1-alkoximinomethyl) dioxazines can be preparedstarting from the corresponding hydroxyphenyl acetates (cf. WO95-04728). Thus, for example(5,6-dihydro[1,4,2]dioxazin-3-yl)-(2-hydroxyphenyl)-methanone-O-methyloxime (1) can be prepared by reacting methyl hydroxyphenylacetate (a)with dihydropyrane, converting the resulting dihydropyranyl ether (b)with t-butyl nitrite into methyl2-[2-(tetrahydropyran-2-yloxy)-phenyl]-2-hydroximinoacetate (c),alkylating this compound with iodomethane to give methyl2-[2-(tetrahydropyran-2-yloxy)-phenyl]-2-methoximino-acetate (d),reacting this with hydroxylamine to give2-[2-(tetrahydropyran-2-yloxy)-phenyl]-2-methoximino-N-hydroxyacetamide(e), cyclizing the latter with dibromoethane to give3-{1-[2-(tetrahydropyran-2-yloxy)-phenyl]-1-methoximino-methyl}-5,6-dihydro-1,4,2-dioxazine(f), and finally removing the tetrahydropyranyl group using acidcatalysis. This synthesis can be illustrated by the following scheme:

A major disadvantage of this process is the fact that a large number ofsteps must be carried out with occasional low yields, which has adecisively adverse effect on cost-efficiency.

It has now been found that novel and known3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines of the general formula(I)

in which

A represents alkyl,

R¹, R², R³ and R⁴ are identical or different and each representsindependently of the others hydrogen, halogen, cyano, nitro, in eachcase optionally halogen-substituted alkyl, alkoxy, alkylthio,alkylsulphinyl or alkylsulphonyl and

Z¹, Z², Z³ and Z⁴ are identical or different and each representsindependently of the others hydrogen, alkyl, halogenoalkyl orhydroxyalkyl, or

Z¹ and Z², or Z¹ and Z³, or Z³ and Z⁴, join with the respective carbonatoms to which they are attached to form a cycloaliphatic ring,

are obtained when (process a) O-hydroxyethyl-O′-alkyl-benzofurandionedioximes of the formula (II)

 in which

A, R¹, R², R³, R⁴, Z¹, Z², Z³ and Z⁴ are each as defined above,

are rearranged, if appropriate in the presence of a diluent and, ifappropriate, in the presence of a base or an acid, and the productsobtained, which may be present as mixtures of stereoisomers, are, ifappropriate, isomerized to give the desired E isomers, if appropriate inthe presence of a diluent and, if appropriate, in the presence of anacid.

In the definitions, the saturated or unsaturated hydrocarbon chains,such as alkyl, including in combination with hetero atoms, such as inalkoxy or alkylthio, are in each case straight-chain or branched.

The compounds which are preparable according to the invention and theirprecursors may, if appropriate, be present as mixtures of variouspossible isomeric forms, in particular of stereoisomers such as, forexample, E and Z isomers, and, if appropriate, also as tautomers. Boththe E and Z isomers, and any mixtures of these isomers, and the possibletautomeric forms are claimed.

The method of process a) according to the invention is preferablyemployed for preparing compounds of the formula (I) in which

A represents methyl, ethyl, n- or i-propyl and

R¹, R², R³ and R⁴ are identical or different and each representsindependently of the others hydrogen, halogen, cyano, nitro, orrepresents alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonylhaving in each case 1 to 6 carbon atoms, each of which is optionallysubstituted by 1 to 5 halogen atoms, and

Z¹, Z², Z³ and Z⁴ are identical or different and each representsindependently of the others hydrogen, alkyl or hydroxyalkyl having ineach case 1 to 4 carbon atoms or halogenoalkyl having 1 to 4 carbonatoms and 1 to five identical or different halogen atoms, or

Z¹ and Z², or Z¹ and Z³, or Z³ and Z⁴, join with the respective carbonatoms to which they are attached to form a cycloaliphatic ring of five,six or seven carbon atoms.

Particular preference is given to preparing compounds of the formula (I)in which

A represents methyl or ethyl and

R¹, R², R³ and R⁴ are identical or different and each representsindependently of the others hydrogen, fluorine, chlorine, bromine,cyano, nitro, methyl, ethyl, n- or i-propyl, n-, i-, s- or t-butyl,methoxy, ethoxy, n- or i-propoxy, methylthio, ethylthio,methylsulphinyl, ethylsulphinyl, methylsulphonyl or ethylsulphonyl,trifluoromethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy,difluorochloromethoxy, trifluoroethoxy, difluoromethylthio,difluorochloromethylthio, trifluoromethylthio, trifluoromethylsulphinylor trifluoromethylsulphonyl,

Z¹, Z², Z³ and Z⁴ are identical or different and each representsindependently of the others hydrogen, methyl, ethyl, n- or i-propyl, n-,i-, s- or t-butyl, hydroxymethyl, trifluoromethyl or trifluoroethyl, or

Z¹ and Z², or Z¹ and Z³, or Z³ and Z⁴, join with the respective carbonatoms to which they are attached to form a cycloaliphatic ring of five,six or seven carbon atoms.

The present invention also relates to novel3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines of the formula (I-a)

in which

A, R¹, R², R³, R⁴, Z¹, Z², Z³ and Z⁴ are each as defined above, butwhere at least one of the substituents R¹, R², R³, R⁴, Z¹, Z², Z³ and Z⁴is different from hydrogen.

The abovementioned general or preferred radical definitions apply bothto the compounds of the formula (I) and also, correspondingly, to thestarting materials or intermediates required in each case for thepreparation.

These radical definitions can be combined with each other at will, i.e.including combinations between the given ranges of preferred compounds.

The formula (II) provides a general definition of theO-hydroxyethyl-O′-alkyl-benzofurandione dioximes required as startingmaterials for carrying out the process a) according to the invention. Inthis formula (II), A, R¹, R², R³, R⁴, Z¹, Z², Z³ and Z⁴ each preferablyor in particular have those meanings which have already been mentionedin connection with the description of the compounds of the formula (I)preparable according to the invention as being preferred or as beingparticularly preferred for A, R¹, R², R³, R⁴, Z¹, Z², Z³ and Z⁴.

The starting materials of the formula (II) have not been disclosedbefore, and as novel compounds they also form part of the subject matterof the present application.

The O-hydroxyethyl-O′-alkyl-benzofurandione dioximes of the formula (II)are obtained when

process b) O-alkyl-benzofurandione dioximes of the formula (III)

 in which

A, R¹, R², R³ and R⁴ are each as defined above

are reacted with an ethane derivative of the formula (IV)

 in which

Y¹ represents halogen, alkylsulphonyloxy, arylsulphonyloxy oralkanoyloxy and

G represents hydrogen, or

Y¹ and G are linked by a single bond, where

Y¹ represents oxygen and

G represents

 or

Y¹ and G together represent a single bond and

Z¹, Z², Z³ and Z⁴ are each as defined above,

if appropriate in the presence of a diluent and, if appropriate, in thepresence of a base.

The formula (III) provides a general definition of theO-alkyl-benzofurandione dioximes required as starting materials forcarrying out the process b) according to the invention. In this formula(III), R¹, R², R³ and R⁴ each preferably or in particular have thosemeanings which have already been mentioned in connection with thedescription of the compounds of the formula (I) preparable according tothe invention as being preferred or as being particularly preferred forR¹, R², R³ and R⁴.

The starting materials of the formula (III) have not been disclosedbefore, and as novel compounds they also form part of the subject matterof the present application.

The O-alkyl-benzofurandione dioximes of the formula (III) are obtainedwhen (process c) ω-nitro-2-hydroxyacetophenone oximes of the formula (V)

in which

A, R¹, R², R³ and R⁴ are each as defined above are reacted with a base,if appropriate in the presence of a diluent, or when (process d)O-alkyl-benzofuranone oximes of the formula (VI)

 in which

A, R¹, R², R³ and R⁴ are each as defined above

are reacted with an alkali metal nitrite or an alkyl nitrite, ifappropriate in the presence of a diluent and, if appropriate, in thepresence of an acid or a base.

The formula (V) provides a general definition of theω-(nitro-2-hydroxyacetophenone oximes required as starting materials forcarrying out the process c) according to the invention. In this formula(V), A, R¹, R², R³ and R⁴ each preferably or in particular have thosemeanings which have already been mentioned in connection with thedescription of the compounds of the formula (I) preparable according tothe invention as being preferred or as being particularly preferred forA, R¹, R², R³ and R⁴.

The starting materials of the formula (V) have not been disclosedbefore, and as novel compounds they also form part of the subject matterof the present application.

The ω-nitro-2-hydroxyacetophenone oximes of the formula (V) are obtainedwhen (process e) ω-nitro-2-hydroxyacetophenones of the formula (VII)

in which

R¹, R², R³ and R⁴ are each as defined above

are reacted with an alkoxyamine of the formula (VIII)

A—O—NH₂  (VIII)

 in which

A is as defined above

or an acid addition complex thereof

if appropriate in the presence of a diluent and, if appropriate, in thepresence of an acid acceptor.

The formula (VII) provides a general definition of theω-nitro-2-hydroxyacetophenones required as starting materials forcarrying out the process e) according to the invention. In this formula(VII), A, R¹, R², R³ and R⁴ each preferably or in particular have thosemeanings which have already been mentioned in connection with thedescription of the compounds of the formula (I) preparable according tothe invention as being preferred or as being particularly preferred forA, R¹, R², R³ and R⁴.

The starting materials of the formula (VII) are known and can beobtained by known methods (Proc.-Indian Acad.Sci.Sect.A, 83, 1976, 238,239, 242; J.Chem.Res.Miniprint, 1978, 865, 877; J.Amer.Chem.Soc.,67<1945>99, 101; Synthesis, 5, 1982, 397-399).

The formula (VI) provides a general definition of theO-alkyl-benzofuranone oximes required as starting materials for carryingout the process d) according to the invention. In this formula (VI), A,R¹, R², R³ and R⁴ each preferably or in particular have those meaningswhich have already been mentioned in connection with the description ofthe compounds of the formula (I) preparable according to the inventionas being preferred or as being particularly preferred for A, R¹, R², R³and R⁴.

The starting materials of the formula (VI) have not been disclosedbefore, and as novel compounds they also form part of the subject matterof the present application.

The O-alkyl-benzofurandione dioximes of the formula (VI) are obtainedwhen (process f) ω-halogeno-2-hydroxyacetophenone oximes of the formula(IX)

in which

A, R¹, R², R³ and R⁴ are each as defined above, and

X represents halogen

are reacted with a base, if appropriate in the presence of a diluent, orwhen (process g) benzofuranones of the formula (X)

 in which

R¹, R², R³ and R⁴ are each as defined above

are reacted with an alkoxyamine of the formula (VIII)—or an acidaddition complex thereof

if appropriate in the presence of a diluent and, if appropriate, in thepresence of an acid acceptor, or when (process h) benzofuranone oximesof the formula (XI)

 in which

R¹, R², R³ and R⁴ are each as defined above

are reacted with an alkylating agent of the formula

A—Y (XII)

in which

A is as defined above and

Y represents halogen, alkylsulphonyloxy, alkoxysulphonyloxy orarylsulphonyloxy,

if appropriate in the presence of a diluent and, if appropriate, in thepresence of a base.

The formula (IX) provides a general definition of theω-halogeno-2-hydroxyacetophenone oximes required as starting materialsfor carrying out the process f) according to the invention. In thisformula (IX), A, R¹, R², R³ and R⁴ each preferably or in particular havethose meanings which have already been mentioned in connection with thedescription of the compounds of the formula (I) preparable according tothe invention as being preferred or as being particularly preferred forA, R¹, R², R³ and R⁴. X represents halogen, preferably chlorine orbromine.

The starting materials of the formula (IX) have not been disclosedbefore, and as novel compounds they also form part of the subject matterof the present application.

The ω-halogeno-2-hydroxyacetophenone oximes of the formula (IX) areobtained when (process i) ω-haloogeno-2-hydroxyacetophenones of theformula (XIII)

in which

R¹, R², R³, R⁴ and X are each as defined above

are reacted with an alkoxyamine of the formula (VIII)—or an acidaddition complex thereof

if appropriate in the presence of a diluent and, if appropriate, in thepresence of an acid acceptor.

The formula (XIII) provides a general definition of theω-halogeno-2-hydroxyacetophenones required as starting materials forcarrying out the process i) according to the invention. In this formula(XIII), R¹, R², R³ and R⁴ each preferably or in particular have thosemeanings which have already been mentioned in connection with thedescription of the compounds of the formula (I) preparable according tothe invention as being preferred or as being particularly preferred forR¹, R², R³ and R⁴. X represents halogen, preferably chlorine or bromine.

The ω-halogeno-2-hydroxyacetophenones of the formula (XIII) are knownand can be prepared by known processes (J. Org. Chem. (1990), 55(14),4371-7 and Synthesis (1988), (7), 545-6).

The formula (X) provides a general definition of the benzofuranonesrequired as starting materials for carrying out the process g) accordingto the invention. In this formula (X), R¹, R², R³ and R⁴ each preferablyor in particular have those meanings which have already been mentionedin connection with the description of the compounds of the formula (I)preparable according to the invention as being preferred or as beingparticularly preferred for R¹, R², R³ and R⁴.

The benzofuranones of the formula (X) are known and can be prepared byknown processes (Friedlaender; Neudoerfer, Chem. Ber. 30<897>1081).

The formula (XI) provides a general definition of the benzofuranoneoximes required as starting materials for carrying out the process h)according to the invention. In this formula (XI), R¹, R², R³ and R⁴ eachpreferably or in particular have those meanings which have already beenmentioned in connection with the description of the compounds of theformula (I) preparable according to the invention as being preferred oras being particularly preferred for R¹, R², R³ and R⁴.

The benzofuranone oximes of the formula (XI) are known and can beprepared by known processes (cf. for example Stoermer, Bartsch, Chem.Ber., 33<1900>3180).

The formula (XII) provides a general definition of the alkylating agentsfurther required as starting materials for carrying out the process h)according to the invention. In this formula (XII), A preferably or inparticular has those meanings which have already been mentioned inconnection with the description of the compounds of the formula (I)preparable according to the invention as being preferred or as beingparticularly preferred for A. Y represents halogen, preferably chlorine,bromine or iodine, alkylsulphonyloxy, preferably methylsulphonyloxy,alkoxysulphonyloxy, preferably methoxysulphonyloxy, or arylsulphonyloxy,preferably 4-tolylsulphonyloxy.

The alkylating agents of the formula (XII) are known chemicals forsynthesis.

The formula (VIII) provides a general definition of the alkoxyaminesfurther required as starting materials for carrying out the processese), g) and i) according to the invention. In this formula (VIII), Apreferably or in particular has those meanings which have already beenmentioned in connection with the description of the compounds of theformula (I) preparable according to the invention as being preferred oras being particularly preferred for A. Preferred acid addition complexesof the alkoxyamines of the formula (VIII) are their hydrochlorides,sulphates and hydrogen sulphates.

The alkoxyamines of the formula (VIII) and their acid addition complexesare known chemicals for synthesis.

The formula (IV) provides a general definition of the ethane derivativesfurther required as starting materials for carrying out the process b)according to the invention. In this formula (IV), Z¹, Z², Z³ and Z⁴ eachpreferably or in particular have those meanings which have already beenmentioned in connection with the description of the compounds of theformula (I) preparable according to the invention as being preferred oras being particularly preferred for Z¹, Z², Z³ and Z⁴. Y¹ representshalogen, preferably chlorine, bromine or iodine, alkylsulphonyloxy,preferably methylsulphonyloxy, arylsulphonyloxy, preferably4-tolylsulphonyloxy, or alkanoyloxy, preferably acetyloxy. G representshydrogen or is attached to Y¹ by a single bond where Y¹ representsoxygen and G represents carbonyl, or G and Y¹ together represent asingle bond.

The ethane derivatives of the formula (IV) are known chemicals forsynthesis.

If the process a) according to the invention is carried out in thepresence of an acid, suitable diluents are all inert organic solvents.These preferably include aliphatic, alicyclic or aromatic hydrocarbonssuch as, for example, petroleum ether, hexane, heptane, cyclohexane,methylcyclohexane, benzene, toluene, xylene or decalin; halogenatedhydrocarbons such as, for example, chlorobenzene, dichlorobenzene,dichloromethane, chloroform, carbon tetrachloride, dichloroethane ortrichloroethane; ethers such as diethyl ether, diisopropyl ether,dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; esters suchas methyl acetate or ethyl acetate, or sulphones such as sulpholane, andany mixtures of the diluents mentioned. Particularly preferred diluentsare ethers such as diethyl ether, 1,2-diethoxyethane or anisole;aromatic hydrocarbons such as, for example, benzene, toluene or xylene.

If the process a) according to the invention is carried out in thepresence of a base, suitable diluents are water and all organicsolvents. These preferably include aliphatic, alicyclic or aromatichydrocarbons such as, for example, petroleum ether, hexane, heptane,cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin;halogenated hydrocarbons such as, for example, chlorobenzene,dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride,dichloroethane or trichloroethane; ethers such as diethyl ether,diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane,tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole;nitriles such as acetonitrile, propionitrile, n- or i-butyronitrile orbenzonitrile; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone orhexamethylphosphoric triamide; esters such as methyl acetate or ethylacetate; sulphoxides such as dimethyl sulphoxide; sulphones such assulpholane; alcohols such as methanol, ethanol, n- or i-propanol, n-,i-, sec- or tert-butanol, ethanediol, propane-1,2-diol, ethoxyethanol,methoxyethanol, diethylene glycol monomethyl ether, diethylene glycolmonoethyl ether, and mixtures thereof with water.

Preferred diluents are water, alcohols such as methanol, ethanol, n- ori-propanol, n-, i-, sec- or tert-butanol, ethanediol, propane-1,2-diol,ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether,diethylene glycol monoethyl ether; and mixtures thereof with water.Particularly preferred diluents in this case are water or alcohols suchas methanol, ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol,ethanediol, propane-1,2-diol, ethoxyethanol, methoxyethanol, diethyleneglycol monomethyl ether, diethylene glycol monoethyl ether, and mixturesthereof with water.

Suitable diluents for carrying out the process b) according to theinvention are water and all organic solvents. These preferably includealiphatic, alicyclic or aromatic hydrocarbons such as, for example,petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane,benzene, toluene, xylene or decalin; halogenated hydrocarbons such as,for example, chlorobenzene, dichlorobenzene, dichloromethane,chloroform, carbon tetrachloride, dichloroethane or trichloroethane;ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether,methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane,1,2-diethoxyethane or anisole; nitriles such as acetonitrile,propionitrile, n- or i-butyronitrile or benzonitrile; amides such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide,N-methylpyrrolidone or hexamethylphosphoric triamide; esters such asmethyl acetate or ethyl acetate; sulphoxides such as dimethylsulphoxide; sulphones such as sulpholane; alcohols such as methanol,ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol, ethanediol,propane-1,2-diol, ethoxyethanol, methoxyethanol, diethylene glycolmonomethyl ether, diethylene glycol monoethyl ether, and mixturesthereof with water. Preferred diluents are water, alcohols such asmethanol, ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol,ethanediol, propane-1,2-diol, ethoxyethanol, methoxyethanol, diethyleneglycol monomethyl ether, diethylene glycol monoethyl ether, and mixturesthereof with water. Particularly preferred diluents are water oralcohols such as methanol, ethanol, n- or i-propanol, n-, i-, sec- ortert-butanol, ethanediol, propane-1,2-diol, ethoxyethanol,methoxyethanol, diethylene glycol monomethyl ether, diethylene glycolmonoethyl ether, and mixtures thereof with water.

Suitable diluents for carrying out the process c) according to theinvention are water and all organic solvents. These preferably includealiphatic, alicyclic or aromatic hydrocarbons such as, for example,petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane,benzene, toluene, xylene or decalin; halogenated hydrocarbons such as,for example, chlorobenzene, dichlorobenzene, dichloromethane,chloroform, carbon tetrachloride, dichloroethane or trichloroethane;ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether,methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane,1,2-diethoxyethane or anisole; ketones such as acetone, butanone, methylisobutyl ketone or cyclohexanone; nitriles such as acetonitrile,propionitrile, n- or i-butyronitrile or benzonitrile; amides such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide,N-methylpyrrolidone or hexamethylphosphoric triamide; esters such asmethyl acetate or ethyl acetate; sulphoxides such as dimethylsulphoxide; sulphones such as sulpholane; alcohols such as methanol,ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol, ethanediol,propane- 1,2-diol, ethoxyethanol, methoxyethanol, diethylene glycolmonomethyl ether, diethylene glycol monoethyl ether, and mixturesthereof with water. Preferred diluents are water, alcohols such asmethanol, ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol,ethanediol, propane-1,2-diol, ethoxyethanol, methoxyethanol, diethyleneglycol monomethyl ether, diethylene glycol monoethyl ether; or nitrilessuch as acetonitrile, propionitrile, n- or i-butyronitrile orbenzonitrile, and mixtures thereof with water.

Suitable diluents for carrying out the process d) according to theinvention are water and all inert organic solvents. These preferablyinclude aliphatic, alicyclic or aromatic hydrocarbons such as, forexample, petroleum ether, hexane, heptane, cyclohexane,methylcyclohexane, benzene, toluene, xylene or decalin; halogenatedhydrocarbons such as, for example, chlorobenzene, dichlorobenzene,dichloromethane, chloroform, carbon tetrachloride, dichloroethane ortrichloroethane; ethers such as diethyl ether, diisopropyl ether, methylt-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles such asacetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile;amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylformanilide, N-methylpyrrolidone or hexamethylphosphorictriamide; organic acids such as acetic acid; esters such as methylacetate, ethyl acetate or butyl acetate; sulphoxides such as dimethylsulphoxide, sulphones such as sulpholane; alcohols such as methanol,ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol, ethanediol,propane-1,2-diol, ethoxyethanol, methoxyethanol, diethylene glycolmonomethyl ether, diethylene glycol monoethyl ether, mixtures thereofwith water or pure water.

Suitable diluents for carrying out the processes e, g and i) accordingto the invention are all inert organic solvents. These preferablyinclude aromatic hydrocarbons such as, for example, benzene, toluene orxylene; halogenated hydrocarbons such as, for example, chlorobenzene,dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride,dichloroethane or trichloroethane; ethers such as diethyl ether,diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane,tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole;amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylformanilide, N-methylpyrrolidone or hexamethylphosphorictriamide; organic acids such as acetic acid; esters such as methylacetate or ethyl acetate; sulphoxides such as dimethyl sulphoxide;sulphones such as sulpholane; alcohols such as methanol, ethanol, n- ori-propanol, n-, i-, sec- or tert-butanol, ethanediol, propane-1,2-diol,ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether,diethylene glycol monoethyl ether, mixtures thereof with water or purewater. Particularly preferred diluents are amides such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide,N-methylpyrrolidone or hexamethylphosphoric triamide; alcohols such asmethanol, ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol,ethanediol, propane-1,2-diol, ethoxyethanol, methoxyethanol, diethyleneglycol monomethyl ether, diethylene glycol monoethyl ether, mixturesthereof with water or pure water. Furthermore, particular preference isalso given to two-phase mixtures such as, for example, water/toluene.

Suitable diluents for carrying out the process f) according to theinvention are all inert organic solvents. These preferably includealiphatic, alicyclic or aromatic hydrocarbons such as, for example,petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane,benzene, toluene, xylene or decalin; halogenated hydrocarbons such as,for example, chlorobenzene, dichlorobenzene, dichloromethane,chloroform, carbon tetrachloride, dichloroethane or trichloroethane;ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether,methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane,1,2-diethoxyethane or anisole; ketones such as acetone, butanone, methylisobutyl ketone or cyclohexanone; nitriles such as acetonitrile,propionitrile, n- or i-butyronitrile or benzonitrile; amides such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide,N-methylpyrrolidone or hexamethylphosphoric triamide; esters such asmethyl acetate or ethyl acetate; sulphoxides such as dimethylsulphoxide; sulphones such as sulpholane; alcohols such as methanol,ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol, ethanediol,propane-1,2-diol, ethoxyethanol, methoxyethanol, diethylene glycolmonomethyl ether, diethylene glycol monoethyl ether, mixtures thereofwith water or pure water, and two-phase mixtures such as, for example,water/toluene. Particularly preferred diluents are aliphatic, alicyclicor aromatic hydrocarbons such as, for example, petroleum ether, hexane,heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene ordecalin; halogenated hydrocarbons such as, for example, chlorobenzene,dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride,dichloroethane or trichloroethane; ethers such as diethyl ether,diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane,tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; andtwo-phase mixtures such as, for example, water/toluene.

Suitable diluents for carrying out the isomerization of the compounds ofthe formula (I) preparable according to the invention are all inertorganic solvents. These preferably include aliphatic, alicyclic oraromatic hydrocarbons such as, for example, petroleum ether, hexane,heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene ordecalin; halogenated hydrocarbons such as, for example, chlorobenzene,dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride,dichloroethane or trichloroethane; ethers such as diethyl ether,diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane,1,2-diethoxyethane or anisole; esters such as methyl acetate or ethylacetate; sulphoxides such as dimethyl sulphoxide; or sulphones such assulpholane.

The isomerization of the compounds of the formula (I) preparableaccording to the invention is, if appropriate, carried out in thepresence of an acid. Suitable acids are all inorganic and organicprotonic and Lewis acids. These include, for example, hydrogen chloride,hydrogen bromide, sulphuric acid, phosphoric acid, formic acid, aceticacid, trifluoroacetic acid, methanesulphonic acid,trifluoromethanesulphonic acid, toluene-sulphonic acid, borontrifluoride (also as etherate), boron tribromide.

The process a) according to the invention is, if appropriate, carriedout in the presence of an acid or a base. Suitable acids are allinorganic and organic protonic and Lewis acids, and also all polymericacids. These include, for example, hydrogen chloride, hydrogen bromide,sulphuric acid, formic acid, acetic acid, trifluoroacetic acid,methanesulphonic acid, trifluoromethanesulphonic acid, toluenesulphonicacid, boron trifluoride (also as etherate), boron tribromide, aluminiumtrichloride, zinc chloride, iron(III) chloride, antimony pentachloride,acidic ion exchangers, acidic alumina and acidic silica gel. Preferenceis given to hydrogen chloride or hydrogen bromide. Suitable bases areall customary inorganic or organic bases. These preferably includealkaline earth metal or alkali metal hydrides, hydroxides, amides,alkoxides, acetates, carbonates or bicarbonates such as, for example,sodium hydride, sodium amide, sodium methoxide, sodium ethoxide,potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammoniumhydroxide, sodium acetate, potassium acetate, calcium acetate, ammoniumacetate, sodium carbonate, potassium carbonate, potassium bicarbonate,sodium bicarbonate or ammonium carbonate, and tertiary amines such astrimethylamine, triethylamine, tributylamine, N,N-dimethylaniline,N,N-dimethylbenzylamine, pyridine, N-methylpiperidine,N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane(DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).Particularly preferred bases are sodium methoxide, sodium ethoxide,potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammoniumhydroxide, and tertiary amines such as trimethylamine, triethylamine,tributylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, pyridine,N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine,diazabicyclooctane (DABCO), diazabicyclononene (DBN) ordiazabicycloundecene (DBU).

The process b) according to the invention is, if appropriate, carriedout in the presence of a suitable acid acceptor. Suitable acid acceptorsare all customary inorganic or organic bases. These preferably includealkaline earth metal or alkali metal hydrides, hydroxides, amides,alkoxides, acetates, carbonates or bicarbonates such as, for example,sodium hydride, sodium amide, sodium methoxide, sodium ethoxide,potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammoniumhydroxide, sodium acetate, potassium acetate, calcium acetate, ammoniumacetate, sodium carbonate, potassium carbonate, potassium bicarbonate,sodium bicarbonate or ammonium carbonate, and tertiary amines such astrimethylamine, triethylamine, tributylamine, N,N-dimethylaniline,N,N-dimethyl-benzylamine, pyridine, N-methylpiperidine,N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane(DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).Particularly preferred bases are sodium methoxide, sodium ethoxide,potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammoniumhydroxide, and tertiary amines such as trimethylamine, triethylamine,tributylamine, N,N-dimethylaniline, N,N-dimethyl-benzylamine, pyridine,N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine,diazabicyclooctane (DABCO), diazabicyclononene (DBN) ordiazabicycloundecene (DBU).

The process c) according to the invention is, if appropriate, carriedout in the presence of a suitable acid acceptor. Suitable acid acceptorsare all customary inorganic or organic bases. These preferably includealkaline earth metal or alkali metal hydrides, hydroxides, amides,alkoxides, acetates, carbonates or bicarbonates such as, for example,sodium hydride, sodium amide, sodium methoxide, sodium ethoxide,potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammoniumhydroxide, sodium acetate, potassium acetate, calcium acetate, ammoniumacetate, sodium carbonate, potassium carbonate, potassium bicarbonate,sodium bicarbonate or ammonium carbonate, and tertiary amines such astrimethylamine, triethylamine, tributylamine, N,N-dimethylaniline,N,N-dimethyl-benzylamine, pyridine, N-methylpiperidine,N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane(DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).Particularly preferred bases are alkaline earth metal or alkali metalhydroxides, alkoxides, carbonates or bicarbonates such as, for example,sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodiumcarbonate, potassium carbonate, potassium bicarbonate, sodiumbicarbonate or ammonium carbonate, and tertiary amines such astrimethylamine, triethylamine, tributylamine, N,N-dimethylaniline,N,N-dimethyl-benzylamine, pyridine, N-methylpiperidine,N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane(DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).

The process d) according to the invention is, if appropriate, carriedout in the presence of an acid or a base. Suitable acids are allinorganic and organic protonic acids. These include, for example,hydrogen chloride, sulphuric acid, phosphoric acid, formic acid, aceticacid, trifluoroacetic acid, methanesulphonic acid,trifluoromethanesulphonic acid or toluenesulphonic acid. Suitable basesare all customary inorganic or organic bases. These preferably includealkaline earth metal or alkali metal hydrides, hydroxides or alkoxidessuch as, for example, sodium hydride, sodium methoxide, sodium ethoxide,potassium tert-butoxide, sodium hydroxide or potassium hydroxide.

The processes e), g) and i) according to the invention are, ifappropriate, carried out in the presence of a suitable acid acceptor.Suitable acid acceptors are all customary inorganic or organic bases.These preferably include alkaline earth metal or alkali metalhydroxides, alkoxides, acetates, carbonates or bicarbonates such as, forexample, sodium methoxide, sodium ethoxide, potassium tert-butoxide,sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodiumacetate, potassium acetate, calcium acetate, ammonium acetate, sodiumcarbonate, potassium carbonate, potassium bicarbonate, sodiumbicarbonate or ammonium carbonate, and tertiary amines such astrimethylamine, triethylamine, tributylamine, N,N-dimethylaniline,N,N-dimethyl-benzylamine, pyridine, N-methylpiperidine,N-methylmorpholine, N,N-dimethylaminopyridine, diazabicyclooctane(DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).

In the practice of the processes a) and b) according to the invention,the reaction temperatures may be varied over a relatively wide range.The reactions are generally carried out at temperatures from −20° C. to100° C., preferably at temperatures from 0° C. to 80° C.

In the practice of the process c) according to the invention, thereaction temperatures may be varied over a relatively wide range. Thereactions are generally carried out at temperatures from 0° C. to 150°C., preferably at temperatures from 20° C. to 100° C.

In the practice of the processes e), g) and i) according to theinvention, the reaction temperatures may be varied over a relativelywide range. The reactions are generally carried out at temperatures from0° C. to 150° C., preferably at temperatures from 0° C. to 80° C.

In the practice of the process d) according to the invention, thereaction temperatures may be varied over a relatively wide range. Thereactions are generally carried out at temperatures from −20° C. to 150°C., preferably at temperatures from 0° C. to 100° C.

In the practice of the process f) according to the invention, thereaction temperatures may be varied over a relatively wide range. Thereactions are generally carried out at temperatures from 0° C. to 200°C., preferably at temperatures from 20° C. to 150° C.

In the practice of the process a) according to the invention forpreparing the compounds of the formula (I), in general 1 to 15 mol,preferably 2 to 6 mol, of base are employed per mole of theO-hydroxyethyl-O′-alkyl-benzofurandione dioxime of the formula (II).

In the practice of the process b) according to the invention forpreparing the compounds of the formula (II), in general 1 to 15 mol,preferably 3 to 6 mol, of ethane derivative of the formula (IV) areemployed per mole of the O-alkyl-benzofurandione dioxime of the formula(III).

In the practice of the process c) according to the invention forpreparing the compounds of the formula (III), in general 1 to 15 mol,preferably 2 to 8 mol, of base are employed per mole of theω-nitro-2-hydroxyacetophenone oxime of the formula (V).

In the practice of the process d) according to the invention forpreparing the compounds of the formula (III), in general 1 to 5 mol,preferably 1 to 3 mol, of alkali metal nitrite or alkyl nitrite areemployed per mole of the O-alkyl-benzofuranone oxime of the formula(VI).

In the practice of the processes e), g) and i) according to theinvention for preparing the compounds of the formula (V), (VI) and (IX),respectively, in general 1 to 15 mol, preferably 1 to 8 mol, of thealkoxyamine of the formula (VIII)—or an acid addition complexthereof—are employed per mole of the ω-nitro-2-hydroxyacetophenone ofthe formula (VII), the benzofuranone of the formula (X) and theω-halogeno-2-hydroxyacetophenone of the formula (XIII), respectively.

In the practice of the process f) according to the invention forpreparing the compounds of the formula (VI), in general 1 to 15 mol,preferably 1 to 5 mol, of base are employed per mole of theω-halogeno-2-hydroxyacetophenone oxime of the formula (IX).

The processes a) to i) according to the invention are generally carriedout at atmospheric pressure. However, it is also possible to carry outthe processes at elevated or reduced pressure—in general between 0.1 barand 10 bar.

In a preferred process variant (A), an ω-nitro-2-hydroxyacetophenone ofthe formula (VII) is converted into an ω-nitro-2-hydroxyacetophenoneoxime of the formula (V) by reaction with an alkoxyamine of the formula(VIII)—or an acid addition complex thereof—if appropriate in a buffersystem such as, for example, sodium acetate/acetic acid, as described inprocess e). Compound (V) is reacted with a base, for example an aqueoussodium bicarbonate solution, to give an O-alkyl-benzofurandione dioximeof the formula (III). The O-alkyl-benzofurandione dioxime of the formula(III) is reacted in basic solution, for example an aqueous alkali metalhydroxide solution, with an ethane derivative of the formula (IV) togive an O-hydroxyethyl-O′-alkyl-benzofurandione dioxime of the formula(II) which, preferably without work-up, reacts further in the basicsolution to give the desired3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazine. This is, ifappropriate, isomerized to the desired E isomer, for example bytreatment with an acid, such as hydrogen chloride, in an organicsolvent, such as ethyl acetate.

In a further preferred process variant (B), anω-halogeno-2-hydroxyacetophenone of the formula (XIII) is converted intoan ω-halogeno-2-hydroxyacetophenone oxime of the formula (IX) byreaction with an alkoxyamine of the formula (VIII)—or an acid additioncomplex thereof—if appropriate in a buffer system such as, for example,sodium acetate/acetic acid, as described in process i). The compound ofthe formula (IX) is cyclized by treatment with a base, for example withsodium bicarbonate in the water/methyl t-butyl ether system, to give anO-alkyl-benzofuranone oxime of the formula (VI). On treatment with analkali metal nitrite or alkyl nitrite in acidic or basic solution, theO-alkyl-benzofuranone oxime of the formula (VI) affords anO-alkyl-benzofurandione dioxime of the formula (III). TheO-alkyl-benzofurandione dioxime of the formula (III) is reacted in basicsolution, for example an aqueous alkali metal hydroxide solution, withan ethane derivative of the formula (IV) to give anO-hydroxyethyl-O′-alkyl-benzofurandione dioxime of the formula (II)which, preferably without work-up, reacts further in the basic solutionto give the desired 3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazine.This is, if appropriate, isomerized to the desired E isomer, for exampleby treatment with an acid, such as hydrogen chloride, in an organicsolvent, such as ethyl acetate.

In a third preferred process variant (C), a benzofuranone of the formula(X) is converted into an O-alkylbenzofuranone oxime of the formula (VI)by reaction with an alkoxyamine of the formula (VIII)—or an acidaddition complex thereof—if appropriate in a buffer system such as, forexample, sodium acetate/acetic acid, as described in process g). Ontreatment with an alkali metal nitrite or alkyl nitrite in acidic orbasic solution, the O-alkyl-benzofuranone oxime of the formula (VI)affords an O-alkyl-benzofuranonedione dioxime of the formula (III). TheO-alkyl-benzofurandione dioxime of the formula (III) is reacted in basicsolution, for example an aqueous alkali metal hydroxide solution, withan ethane derivative of the formula (IV) to give anO-hydroxyethyl-O′-alkyl-benzofurandione dioxime of the formula (II)which, preferably without work-up, reacts further in the basic solutionto give the desired 3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazine.This is, if appropriate, isomerized to the desired E isomer, for exampleby treatment with an acid, such as hydrogen chloride, in an organicsolvent, such as ethyl acetate.

It is very surprising that the processes according to the invention, inparticular when combined, yield high purity products in high yields. Itis particularly surprising that compounds of the general formula (V)readily cyclize with elimination of water even in the presence of waterat temperatures as low as room temperature on treatment with bases togive high yields of compounds of the formula (III) and can be isolatedin high purity simply by filtration. According to the known literature,under these conditions only a deprotonation of the compounds of theformula (V) was to be expected. Furthermore, it is particularlysurprising that the compounds of the formula (III) can be reacted withepoxides under alkaline conditions, without any problems, to givecompounds of the formula (II) which in turn, if appropriate even withoutwork-up, immediately cyclize to the desired3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines. Chem. Ber. 1902, 1640,for example, describes that benzofurandione monooximes are cleaved togive salicylic acid derivatives or hydroxyphenylglyoxalic acidderivatives by treatment both with acids and with bases. Thus, it wouldhave been more likely to expect the compounds of the formula (III) todecompose likewise under the given reaction conditions. The smoothnitrosation of the compounds of the formula (VI) (process d) is alsosurprising, since a nitrosation of methyl or methylene groups which arelocated α to oximes, in contrast to methyl or methylene groups which arelocated α to keto groups, has not been described before.

The processes according to the invention have a number of advantages.Thus, they allow the preparation of a large quantity of3-(1-hydroxyphenyl-1-alkoximinomethyl)dioxazines in high yields and highpurities. It is a further advantage that the ethane derivatives of theformula (IV), the ω-nitro-2-hydroxyacetophenones of the formula (VII),the benzofuranones of the formula (X), and theω-halogeno-2-hydroxyacetophenones of the formula (XIII) required asstarting materials are easily obtainable at low cost, even in largeramounts.

PREPARATION AND PROCESS EXAMPLES Example 1 Process Variant (A)

Step 1

Compound (V-1)

Process e)

At 20° C., 73.5 g (0.88 mol) of methoxyamine hydrochloride are added toa solution of 80.0 g (0.44 mol) of o-hydroxy-ω-nitroacetophenone in 500ml of methanol, and the mixture is stirred at 45 to 50° C. for 8 to 12hours. The solution is cooled to 20° C., poured into 1 l of ice-waterand stirred for one hour. The crystalline product is filtered off andwashed with 500 ml of water a little at a time and dried at 40° C. in avacuum drying cabinet. 72 g (74.6% of theory) of1-(2-hydroxyphenyl)-2-nitro-ethanone O-methyl-oxime are obtained as amixture of stereoisomers.

HPLC: logP=1.87 (12.3%), 2.27 (83.5%).

Step 2

Compound (III-1)

Process c)

71.8 g of 1-(2-hydroxy-phenyl)-2-nitro-ethanone O-methyl-oxime are addedto a solution of 121 g (0.342 mol) of sodium bicarbonate in 700 ml ofwater. Within 30 minutes, the mixture is heated to 90-95° C., on whichundissolved starting material melts and reacts and the productcrystallizes out. The mixture is cooled to 20° C. and the product isfiltered off, washed with 500 ml of water a little at a time andair-dried. 57.4 g (91.3% of theory) of benzofuran-2,3-dione3-(O-methyl-oxime) 2-oxime are obtained as a mixture of twostereoisomers.

HPLC: logP=1.56 (28.4%), 1.72 (71.6%).

Step 3

Compound (II-1)

Process b)

At 20° C., 264.3 g (6.0 mol) of ethylene oxide are passed into asolution of 192.2 g (1.0 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime)2-oxime in 2 l of water over a period of 85 minutes. The solution iscooled to 5° C. and 70 g (1.06 mol) of sodium hydroxide pellets areadded, on which the temperature increases to 10° C. The mixture isstirred without further cooling for another 165 minutes and theprecipitate that has formed is filtered off with suction, washed with500 ml of ice-water a little at a time and dried at 40° C. in a vacuumdrying cabinet. 143.0 g (61% of theory) of benzofuran-2,3-dione2-[O-(2-hydroxy-ethyl)-oxime]3-(O-methyl-oxime) are obtained as amixture of two stereoisomers.

HPLC: logP—1.65 (0.5%), 1.79 (99.5%).

Step 4

Compound (I-1)

Process a)

A solution of 25.6 g (0.1084 mol) of benzofuran-2,3-dione2-[O-(2-hydroxy-ethyl)-oxime] 3-(O-methyl-oxime) and 14.2 g (0.216 mol)of potassium hydroxide pellets in 250 ml of water is stirred at 60° C.for 195 minutes. The solution is cooled to 10° C. and acidified to pH5-6 with glacial acetic acid. The crystalline product is filtered offwith suction, washed with 200 ml of water a little at a time and driedat 45° C. in a vacuum drying oven. 17.7 g (67.7% of theory) ofE-(5,6-dihydro-[1,4,2]dioxazin-3-yl)-(2-hydroxy-phenyl)-methanoneO-methyl-oxime are obtained.

HPLC: logP=1.22.

Example 2

Compound (I-1)

One-pot variant of processes a) and b)

At 20° C., 19.8 g (0.3 mol) of potassium hydroxide pellets are added toa suspension of 38.4 g (0.2 mol) of benzofuran-2,3-dione3-(O-methyl-oxime) 2-oxime in 400 ml of water and the mixture wasstirred for 30 minutes, on which a solution forms. At 20° C., 17.6 g(0.4 mol) of ethylene oxide are introduced over a period of 75 minutes,and the mixture is stirred at 20° C. overnight, on which a precipitateforms. The mixture is then stirred at 60° C. for 11 hours, on which theprecipitate redissolves. The solution is cooled and acidified to pH 5-6with glacial acetic acid. The crystalline product is filtered off withsuction, washed with 300 ml of water a little at a time and dried at 45°C. in a vacuum drying cabinet. 19.6 g (39.3% of theory) of(5,6-dihydro-[1,4,2]dioxazin-3-yl)-(2-hydroxy-phenyl)-methanoneO-methyl-oxime are obtained.

HPLC: logP=1.24 (E isomer 94.2%); 2.05 (Z isomer 0.6%).

Example 3

Compound (I-1)

Isomerization

112 g of hydrogen chloride are introduced into a solution of 806 g (4.19mol) of (5,6-dihydro-[1,4,2]dioxazin-3-yl)-(2-hydroxy-phenyl)-methanoneO-methyl-oxime (33.3% Of Z isomer, 66.6% of E isomer) over a period of60 minutes, on which the solution warms from 20° C. to 27° C. Themixture is stirred at 20° C. for another 18 hours and subsequentlyconcentrated under reduced pressure. The residue is dried at 40° C. in avacuum drying cabinet. 806 g (100% of theory) of(5,6-dihydro-[1,4,2]dioxazin-3-yl)-(2-hydroxy-phenyl)-methanoneO-methyl-oxime with an E isomer content of 94.8% (HPLC) are obtained.

Example 4

Compound (III-1)

Process d)

3.92 g (0.035 mol) of potassium tert-butoxide are dissolved in 40 ml oftert-butanol. A solution of 5.7 g (0.035 mol) of benzofuran-3-oneO-methyl-oxime and 7.2 g (0.07 mol) of tert-butyl nitrite in 10 ml oftert-butanol is added to this solution. The mixture is stirred withoutcooling for two hours and then admixed with 20 ml of 2N aqueoushydrochloric acid. The crystalline product is filtered off, washedrepeatedly with water and dried in a desiccator. 3.19 g (47.1% oftheory) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime are obtainedas a mixture of two stereoisomers comprising 86.33% of isomer A and12.98% of isomer B (HPLC).

¹H NMR spectrum (DMSO-d₆/TMS): δ=4.10 (3H, isomer B); 4.11 (3H; isomerA); 7.21/7.24/7.26 (1H); 7.31/7.34 (1H); 7.51/7.53/7.56 (1H); 7.63/7.65(1H, isomer B) 8.02/8.05 (1H, isomer A); 11.36 (1H, isomer A); 11.75(1H, isomer B) ppm.

Identical results are obtained when butyl acetate is used instead oftert-butanol.

Example 5

Compound (III-1)

Process d)

At −10° C., 2 g (0.019 mol) of tert-butyl nitrite are added dropwise to30 ml of ethyl acetate which is saturated with dry hydrogen chloride,and the mixture is stirred at this temperature for 15 minutes. At −10°C., 1.6 g (0.0098 mol) of benzofuran-3-one O-methyl-oxime dissolved in 5ml of ethyl acetate are then added, the temperature is allowed toincrease to 0° C. and the mixture is stirred at this temperature for 30minutes. The crystalline product is filtered off, affording 1.08 g ofcrystalline benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime as a mixtureof two stereoisomers comprising, according to HPLC analysis, 54.7% (56%of theory) of isomer B and 42.9% of isomer A.

¹H NMR spectrum (CDCl₃/TMS): δ=4.10 (3H, isomer B); 4.11 (3H, isomer A);7.21-7.26 (1H); 7.31-7.35 (1H); 7.5-7.65 (2H, isomer B+1H, isomer A);8.02-8.05 (1H, isomer A); 11.36 (1H, isomer A); 11.75 (1H, isomer B)ppm.

5-Methylbenzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime (III-2) wasobtained in a similar fashion.

¹H NMR spectrum (CDCl₃/TMS): δ=2.24 (3H, isomer B); 2.25 (3H, isomer A)ppm.

Example 6

Compound (VI-1)

Process f)

74 g (0.303 mol) of 2-bromo-1-(2-hydroxy-phenyl)-ethanone O-methyl-oximeare dissolved in 350 ml of tert-butyl methyl ether and heated underreflux with a solution of 40 g (0.377 mol) of sodium carbonate in 400 mlof water with vigorous stirring for 5 days. The organic phase isseparated off and dried over sodium sulphate and the solvent isdistilled off under reduced pressure, affording 45.5 g (82.8% of theory,90% of Z isomer according to HPLC analysis) of crude benzofuran-3-oneO-methyl-oxime.

¹H NMR spectrum (DMSO-d₆/TMS): δ=3.93 (3H); 5.16 (2H); 7.0-7.07 (2H);7.39-7.45 (1H); 7.54-7.57 (1H) ppm.

5-Methylbenzofuran-3-one O-methyl-oxime (VI-2) was obtained in a similarfashion.

GC/MS: M⁺=177; HPLC: logP=2.88.

Example 7

Compound (VI-1)

Process g)

6.7 g (0.05 mol) of benzofuran-3-one together with 4.2 g (0.05 mol) ofO-methylhydroxylamine hydrochloride and 4.1 g (0.05 mol) of sodiumacetate in 50 ml of methanol are heated under reflux for 3 hours. Thesolvent is distilled off under reduced pressure and the reaction mixtureis poured into water and extracted with ethyl acetate. The organic phaseis washed with saturated aqueous sodium carbonate solution. The organicphase is dried over sodium sulphate and the solvent is distilled offunder reduced pressure. 7.27 g (89.2% of theory) of crudebenzofuran-3-one O-methyl-oxime are obtained. For analysis, the crudeproduct is distilled at 2 torr and 70° C. using a Kugelrohr. An oil isobtained which, both according to NMR analysis and according to HPLCanalysis, comprises two stereoisomers (79% of isomer B and 21% of isomerA).

¹H-NMR spectrum (DMSO-d₆/TMS): δ=3.93 (3H, isomer B); 3.93 (3H, isomerA); 5.11 (2H, isomer A); 5.16 (2H, isomer B); 7.0-7.07 (2H); 7.39-7.45(1H); 7.54/7.57 (1H, isomer B); 7.95-8.02 (1H, isomer A) ppm.

Example 8

Compound (VI-1)

Process h)

3.7 g of benzofuran-3-one oxime are dissolved in 15 ml ofdimethylformamide. At 20° C., 1 g of sodium hydride (60%) is added andthe mixture is stirred until the evolution of gas ceases. 3.15 g ofdimethyl sulphate are then added dropwise and the mixture is stirred at20° C. for 24 hours. The reaction mixture is poured into water,extracted with ethyl acetate, the organic phase is dried over sodiumsulphate and the solvent is distilled off under reduced pressure. Theresidue is chromatographed over silica gel using n-hexane/acetone (4:1).1.7 g (42% of theory) of benzofuran-3-one O-methyl-oxime are obtained asan oil.

¹H-NMR spectrum (DMSO-d₆/TMS): δ=3.93 (3H); 5.16 (2H); 7.0-7.07 (2H);7.39-7.45 (1H); 7.54/7.57 (1H) ppm.

Example 9

Compound (IX-1)

Process i)

107.5 g (0.5 mol) of ω-bromo-2-hydroxy-acetophenone in 500 ml ofmethanol together with 41.75 g (0.5 mol) of O-methylhydroxylaminehydrochloride are heated under reflux for 4 hours. The methanol isdistilled off under reduced pressure and the residue is admixed with 500ml of water and extracted with 4 times 100 ml of ethyl acetate. Theorganic phase is dried over sodium sulphate and the solvent is distilledoff under reduced pressure. At 0° C., the residue is stirred withpetroleum ether, affording 74 g (52% of theory) of crystalline2-bromo-1-(2-hydroxy-phenyl)-ethanone O-methyl-oxime as a mixture of twostereoisomers (53% of isomer B and 33% of isomer A).

¹H NMR spectrum (CDCl₃/TMS): δ=3.98 (3H, isomer B); 3.99 (3H, isomer A);4.53 (3H, isomer A); 4.69 (3H, isomer B); 6.85-6.93 (2H); 7.26-7.35(2H); 10.21 (1H, isomer B); 10.25 (1H, isomer A) ppm.

2-Chloro-1-(2-hydroxy-5-methyl-phenyl)-ethanone O-methyl-oxime (IX-2)was obtained in a similar fashion.

¹H NMR spectrum (CDCl₃/TMS): δ=2.32 (s, 3H); 4.08 (s, 3H) ppm.

Similar to Examples 1 and 2, and according to the general description ofthe process a) according to the invention, the compounds of the formula(I-a) listed in Table 1 were obtained:

TABLE I mp. Compound R³ Z¹ Z² (° C.) logP NMR* 2 —C₂H₅ —H —H 1.88 1.23(m, 3H); 2.62 (m, 2H; 4.10 (s, 3H); 4.21 (m, 2H); 4.49 (m, 2H) 3 —CH₃ —H—H 1.52 2.29 (s. 3H); 4.10 (s, 3H); 4.21 (m, 2H); 4.49 (m, 2H) 4 —H —CH₃—H 136 1.49 5 —H —C₂H₅ —H 134 1.82 6 —H —CH₃ —CH₃ 1.68 *The ¹H NMRspectra were recorded in deuterochloroform (CDCl₃) orhexadeuterodimethyl sulphoxide (DMSO-d₆) using tetramethylsilane (TMS)as internal standard. Stated is the chemical shift as δ value in ppm.

Similar to Example 1, compound (II-1), and according to the generaldescription of the process b) according to the invention, the compoundsof the formula (II-a) listed in Table 2 were obtained:

TABLE 2 Compound R³ Z¹ Z² mp. (° C.) log P (II-2) —CH₃ —H —H 2.10 (II-3)—C₂H₅ —H —H 2.46 (II-4) —H —H —CH₃ 81 2.04 (II-5) —H —CH₃ —CH₃ 72 2.27(II-6) —H —H —C₂H₅ 74 2.39

What is claimed is:
 1. An O-alkyl-benzofurandione dioxide of the formula(III): wherein A represents alkyl; and R¹, R², R³ and R⁴ are identicalor different and each represents independently of the others hydrogen,halogen, cyano, nitro, in each case optionally halogen-substitutedalkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl.
 2. Aω-halogeno-2-hydroxy acetophenone oxime of the formula (IX):

wherein X represents halogen; A represents alkyl; and R¹, R², R³ and R⁴are identical or different and each represents independently of theothers hydrogen, halogen, cyano, nitro, in each case optionallyhalogen-substituted alkyl, alkoxy, alkylthio, alkylsulphinyl oralkylsulphonyl.